In the central nervous system, the majority of the active form of thyroid hormone, T3, derives from the cellular uptake and intracellular 5'-monodeiodination of T4 by type II 5'-monodeiodinase (DII). In the adult rat brain, high DII activity is present in the arcuate nucleus/median eminence region with minimal activity in the paraventricular nucleus where the central thyroid-regulating neurons, the thyrotropin releasing hormone (TRH)-containing cells are located. DII-producing cells are both astrocytes and tanycytes and provide a network of processes arcing between the third ventricle and the basal surface of the brain and the portal vessels of the median eminence. Arcuate nucleus DII-producing glial cells may actively participate in metabolism regulation, because they are in close proximity to T3-targeted neurons, including those producing neuropeptide Y (NPY), agouti-related protein (AgRP) and pro-opiomelanocortin (POMC), all of which project onto the paraventricular TRH cells and considered as primum movens in metabolism regulation. In support of this proposition, we found that arcuate nucleus DII activity is elevated during fasting, a paradigm during which negative feedback of circulating thyroid hormones is diminished in the hypothalamus. The aforementioned observations gave impetus to our hypothesis that it is activation of arcuate nucleus DII by diminishing leptin and elevating corticosterone levels that disrupts normal thyroid feedback during short-term food deprivation. The following Specific Aims will test our hypotheses: Specific Aim 1. Is increased arcuate nucleus DII activity responsible for the loss of thyroid hormone feedback in fasted rats? Specific Aim 2. Does the inactivation of DII by lOP infusion during fasting suppress activation of NPY/AgRP and suppression of POMC neurons? Specific Aim 3. Do leptin and glucocorticoids affect the mRNA levels and the enzymatic activity of 5'-iodothyronine deiodinase type II in the hypothalamus of fasted rats? The results of these studies will shed light on the role of DII in central metabolism regulation offering a novel hypothalamic target for drug development in the fighting of metabolic disorders, including diabetes, obesity and the so called "nonthyroidal illness syndrome" in humans.